pregabalin and Agoraphobia

Pregabalin, a compound with a novel mechanism of action (MOA), has demonstrated efficacy as an adjunctive treatment for epilepsy and in several neuropathic pain models. Multiple generalized anxiety disorder (GAD) clinical trials have shown that pregabalin has efficacy similar to the benzodiazepines and venlafaxine. Onset of anxiolytic effect was observed as early as Week 1 of treatment, and efficacy was seen in treating both psychic and somatic anxiety symptoms. Pregabalin binds potently and selectively to the alpha-2-delta subunit of "hyper-excited" voltage-gated calcium channels (VGCCs). The binding of pregabalin to VGCCs changes their conformation, reducing calcium influx at nerve terminals. Pregabalin only modulates the release of excitatory neurotransmitters in "hyper-excited" neurons, restoring them to normal physiological state. This newly defined MOA is believed to confer on pregabalin its anxiolytic, analgesic, and anticonvulsant properties. Thus, pregabalin may offer physicians an effective and well-tolerated therapy for GAD, which differs from existing treatments.

Topics: Agoraphobia; Animals; Anti-Anxiety Agents; Clinical Trials as Topic; gamma-Aminobutyric Acid; Humans; Pain; Pregabalin

To review pregabalin's pharmacology, pharmacokinetics, efficacy, and adverse effects in the treatment of neuropathic pain, epilepsy, and anxiety.. A MEDLINE search (1993-October 2005) for peer-reviewed English-language publications was performed. Abstracts from professional meetings were also included. Key terms were anxiety, diabetic neuropathy, epilepsy, neuropathic pain, postherpetic neuralgia, pregabalin, and seizures.. Basic pharmacology data were extracted from animal studies; pharmacokinetic data were extracted from human studies. Multicenter, double-blind, placebo-controlled, parallel-group studies were included to describe the efficacy and adverse effects of pregabalin.. Pregabalin is a new agent that exerts its pharmacodynamic effect by modulating voltage-gated calcium channels. Pregabalin has a linear pharmacokinetic profile. It is completely absorbed, not bound to plasma proteins, not metabolized, and eliminated unchanged through the kidneys. Doses must be adjusted in patients with renal insufficiency. Clinical trials showed that pregabalin is effective in neuropathic pain associated with postherpetic neuralgia, diabetic peripheral neuropathy, in partial epilepsy as adjunctive therapy, and in generalized and social anxiety disorders. The most common adverse effects were dizziness and somnolence. Few serious adverse effects were reported. Pregabalin should not be discontinued rapidly.. Pregabalin is an effective and safe analgesic, antiepileptic, and anxiolytic medicine. It will provide a new treatment option for patients with neuropathic pain and partial epilepsy.

Topics: Agoraphobia; Anxiety; Diabetic Neuropathies; Epilepsy; gamma-Aminobutyric Acid; Herpesviridae Infections; Humans; Multicenter Studies as Topic; Neuralgia; Neurotransmitter Agents; Pain; Peripheral Nervous System Diseases; Pregabalin; Randomized Controlled Trials as Topic; Seizures

Pfizer is developing pregabalin, a follow-up compound to its GABA agonist gabapentin, for the potential treatment of several central nervous system (CNS) disorders including epilepsy, neuropathic pain, anxiety and social phobia [286425]. By December 2000, Pfizer anticipated filing an NDA for pregabalin for seven major indications (beginning with neuropathic pain and add-on epilepsy), with the FDA by the end of 2001. Filings for generalized anxiety disorder (GAD), social anxiety disorder and fibromyalgia are expected to take place in 2002, and filings for epilepsy monotherapy and panic disorders are expected to take place in early- and late-2003, respectively [336918], [393182], [399956]. By January 2001, pregabalin was in phase II development in Japan for the potential treatment of neuropathic pain, with an anticipated approval date of 2005 [394827]. However, following analysis by the FDA of a mouse study that showed incidence of a specific tumor type, Pfizer announced in February 2001, that it is restricting the use of pregablin in some clinical patients [398726] and it has frozen trials for neuropathic pain [398785]. In April 2001, Morgan Stanley Dean Witter predicted potential sales of $350 million in 2002, rising to $1750 million in 2006, with peak sales in excess of $2000 million [406923].

Topics: Agoraphobia; Animals; Anticonvulsants; Clinical Trials as Topic; Contraindications; GABA Agonists; gamma-Aminobutyric Acid; Humans; Pain; Pregabalin; Structure-Activity Relationship

The objective of the study was to evaluate the response of generalized anxiety disorder (GAD) patients with prominent gastrointestinal (GI) symptoms to pregabalin (PGB) treatment. Data were pooled from six double-blind, placebo (PBO)-controlled, 4-6 week trials in outpatients who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria for GAD with a minimum Hamilton Anxiety Rating Scale (HAM-A) total score of 20. Treatment response was evaluated for three PGB fixed-dosage groups: 150, 300-450, and 600 mg/day, and for fixed doses of a benzodiazepine (alprazolam, 1.5 mg/day; lorazepam, 6 mg/day). A GI-high subgroup (high GI symptomatology) was defined by a baseline HAM-A item-11 (GI) score of 3 or greater (severe/very severe). At baseline, 301 patients (16.2%) met criteria for the GI-high subgroup. Baseline characteristics were approximately similar for the four study treatments in the GI-high subgroup. For the GI-high subgroup, last observation carried forward (LOCF) endpoint reduction in HAM-A was significantly higher on PGB-300/450 -13.8+/-1.2 and PGB-600 -14.7+/-1.0 compared with PBO -10.1+/-0.9 (P<0.01 for both comparisons); but the difference on PGB-150 did not achieve significance (-13.5+/-1.6; P=0.083). Also in the GI-high subgroup, endpoint reduction in HAM-A item-11 was significantly higher on PGB-300/450 compared with PBO (-1.93+/-0.16 vs. -1.52+/-0.13; P=0.04), but did not achieve significance on PGB-600 mg (-1.89+/-0.14; P=0.06), or PGB-150 mg (-1.90+/-0.23; P=0.16). In the GI-high subgroup, treatment with a benzodiazepine was not associated with significant endpoint reduction in either the HAM-A total score or the HAM-A item-11 score. Patients in the GI-high subgroup had higher discontinuation rates when treated with benzodiazepines, whereas treatment with PGB 300-600 mg/day was not associated with treatment-emergent worsening in GI symptoms compared with placebo. Treatment with PGB improved overall levels of anxiety, as well as specifically improving GI symptoms.

Topics: Adult; Agoraphobia; Analgesics; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Data Interpretation, Statistical; Double-Blind Method; Endpoint Determination; Female; gamma-Aminobutyric Acid; Gastrointestinal Diseases; Humans; Male; Middle Aged; Pregabalin; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic